Current pharmaceutical biotechnology最新文献

{"title":"Anti-Cancer Properties and Mechanistic Insights of Dihydroquercetin.","authors":"Cheng Zhang, Yuqiao Zeng, Bing Wu, Li Wang, Pengfei Wu, Ao Shen, Likun Wang","doi":"10.2174/0113892010366947250415051408","DOIUrl":"https://doi.org/10.2174/0113892010366947250415051408","url":null,"abstract":"<p><p>Dihydroquercetin (DHQ), also known as taxifolin, is a naturally occurring flavonoid compound that serves as an active pharmaceutical ingredient. It is commercially available in the form of dietary supplements. As the reduced form of quercetin, DHQ contains five phenolic hydroxyl groups. This compound is capable of chelating transition metal ions, thereby effectively scavenging free radicals and detoxifying harmful substances while modulating enzyme activities. Consequently, DHQ exhibits potent antioxidant, anti-inflammatory, antiviral, and antibacterial properties. Given its significant pharmacological potential, DHQ exhibits anti-tumor activity against various malignant tumors, including breast cancer, gastric cancer, hepatocellular carcinoma, colonic neoplasms, melanoma, and prostate cancer. DHQ inhibits tumor occurrence and progression by regulating multiple signaling pathways, such as wnt/β-catenin, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), mammalian target of rapamycin (mTOR), transforming growth factor-beta (TGF-β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF- κB), and mitogen-activated protein kinase (MAPK). The anti-tumor mechanisms of DHQ include inhibition of cell proliferation, invasion, and migration; induction of cell cycle arrest, activation of autophagy, apoptosis, epigenetic modification, suppression of epithelial-mesenchymal transition (EMT), enhancement of chemotherapy efficacy, and augmentation of immune function. In particular, DHQ potentiates the efficacy of chemotherapy drugs and augments immune function. Based on a systematic review of the pharmacological properties and anti-tumor mechanisms of DHQ across multiple malignant tumors, we conclude DHQ to be a promising natural compound with significant potential for anti-tumor therapy.</p>","PeriodicalId":10881,"journal":{"name":"Current pharmaceutical biotechnology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safflower Extract Mitigates MIRI in Rats by Modulating TLR-4/NF-κB Signaling Pathway, Demonstrating Protective Effects.","authors":"Mingling Deng, Jing Yang, Aimaiti Julaiti, Yue Dong, Yunfang Deng, Zhaoju Wang","doi":"10.2174/0113892010356035250417022534","DOIUrl":"https://doi.org/10.2174/0113892010356035250417022534","url":null,"abstract":"<p><strong>Background: </strong>Myocardial ischemia-reperfusion injury (MIRI) exacerbates tissue damage following the restoration of coronary blood flow after ischemia. The TLR-4/NF-κB signaling pathway plays a crucial role in the pathogenesis of MIRI. This study investigated the therapeutic efficacy of safflower extract in mitigating MIRI and its modulation of TLR-4/NF-κB signaling in rats.</p><p><strong>Methods: </strong>Adult male Sprague-Dawley rats were subjected to 30 minutes of myocardial ischemia followed by 2 h of reperfusion. Safflower extract was administered intravenously at doses of 2, 4, and 8 mg/kg 15 minutes before ischemia and 1 minute before reperfusion. Infarct size was assessed using TTC staining. Serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH) were measured. Pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) were quantified using ELISA. TLR-4 and NF-κB mRNA and protein expression were evaluated using qRT-PCR and western blotting, respectively. Histopathological changes were assessed using H&E staining.</p><p><strong>Results: </strong>Safflower extract effectively reduced myocardial infarct size in a dose-dependent manner, with the highest dose providing the greatest benefit. Treatment with safflower extract significantly lowered the elevated levels of serum CK and LDH caused by ischemia-reperfusion (I/R) injury, bringing these biochemical markers closer to normal values. In addition, safflower extract decreased the levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in myocardial tissue, showing a clear dose-response relationship. Analysis through qRT-PCR and western blot confirmed that safflower extract downregulated the expression of TLR4 and NF-κB at both the transcriptional and protein levels. Histological studies further supported these findings, demonstrating that safflower extract improved myocardial tissue architecture, maintained cardiomyocyte structure, and reduced inflammatory cell infiltration.</p><p><strong>Conclusions: </strong>Safflower extract provides significant cardioprotection against MIRI by modulating the TLR-4/NF-κB-mediated inflammatory response. These findings suggest that safflower extract may be a potential therapeutic agent for mitigating the effects of myocardial ischemiareperfusion injury.</p>","PeriodicalId":10881,"journal":{"name":"Current pharmaceutical biotechnology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Baicalin-Targeted ZHX2/MMP14 Axis Attenuates Cirrhotic Portal Hypertension.","authors":"Hui Wang, Jiawei Ma, Jinghe Liu, Xiao Liu, Xiao Cai, Yufei Chang","doi":"10.2174/0113892010349745250416105433","DOIUrl":"https://doi.org/10.2174/0113892010349745250416105433","url":null,"abstract":"<p><strong>Background: </strong>Given the high mortality associated with Cirrhotic Portal Hypertension (CPH) worldwide, this study investigates the mechanism by which baicalin (BA), known for its beneficial effects on cirrhosis, alleviates CPH.</p><p><strong>Methods: </strong>The CPH model was established in Sprague-Dawley (SD) rats, followed by 4-week oral administration of 30 and 60 mg/kg/day BA. SD rats were randomly assigned to four groups (n=6/group): Con, Model, BA-30, and BA-60. Portal vein smooth muscle cells (PVSMCs, extracted from SD rats, n=6) were incubated with 5, 10 and 20 μmol/L BA. The levels of liver function indicators and von Willebrand factor (vWF) were determined by biochemical and immunohistochemical analyses, respectively. The portal pressure (PP) was examined. The liver fibrosis was detected by Sirius red staining. The levels of fibrosis-, angiogenesis- and proliferation- related indicators, zinc fingers and homeoboxes 2 (ZHX2), and matrix metallopeptidase 14 (MMP14) were quantified by Western blot. The levels of and interaction between ZHX2 and MMP14 were separately measured by quantitative real-time polymerase chain reaction (qRTPCR) and luciferase reporter assay. The proliferation and migration of PVSMCs were assessed by EdU staining and scratch test, respectively.</p><p><strong>Results: </strong>BA up-regulated ZHX2 and down-regulated MMP14 (P<0.001). BA concentrationdependently suppressed liver fibrosis, PP, and angiogenesis in the liver tissue, as well as PVSMC proliferation and migration, while enhancing liver function (P<0.05). Further, according to the GRNdb database and luciferase reporter assay, ZHX2 is bound with the promoter of MMP14. ZHX2 could suppress the MMP14 level (P<0.001). ZHX2 silencing reversed the effects of BA treatment on the proliferation and migration of PVSMCs, whereas MMP14 silencing could further offset the role of ZHX2 silencing in the BA-treated PVSMCs (P<0.05).</p><p><strong>Conclusion: </strong>BA up-regulates ZHX2 to reduce the level of MMP14 and alleviate CPH. Understanding the mechanisms of BA in CPH may provide a foundation for novel interventions to attenuate CPH.</p>","PeriodicalId":10881,"journal":{"name":"Current pharmaceutical biotechnology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selenium Alleviates Oxidative Stress and Inflammation to Promote Postpartum Uterine Recovery via GPX1/GPX4/NRF2 Pathway in Mice.","authors":"Xiangping Li, Peng Li, Pingzhi Wang","doi":"10.2174/0113892010371042250416035948","DOIUrl":"https://doi.org/10.2174/0113892010371042250416035948","url":null,"abstract":"<p><strong>Background: </strong>Selenium is an important trace element that plays crucial roles in metabolism, immune function, and antioxidant defense. As an antioxidant, selenium helps to alleviate postpartum uterine inflammation and promotes uterine recovery. However, the exact mechanism underlying the role of selenium in postpartum uterine recovery is not fully understood.</p><p><strong>Objective: </strong>This study aimed to identify the underlying mechanism and examine how selenium enhances postpartum uterine healing.</p><p><strong>Methods: </strong>Female ICR mice aged 8 weeks were classified into five groups: control, postpartum model, low-dose selenium (100 nm), medium-dose selenium (200 nm), and high-dose selenium (400 nm). Endometrial morphology was evaluated by hematoxylin and eosin (H&E) staining. Oxidative stress markers, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and malondialdehyde (MDA), and inflammatory factors, including tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), were measured using commercially available kits. GPX1, GPX4, and nuclear factor erythroid 2-related factor 2 (NRF2) expression were determined using real-time PCR and WB.</p><p><strong>Results: </strong>We found damage and bleeding points in the endometrium and destruction of the ultrastructure of endometrial cells in the postpartum model group; however, mice treated with a high dose (400 nm) of selenium showed alleviated levels of pathological alteration in the endometrium. In addition, the levels of MDA in the postpartum mice group increased, while the SOD, CAT, and GPX levels decreased; however, changes in these oxidative stress markers were reversed after selenium treatment. For inflammatory factors, high levels of TNF-α and IL-1β were observed in postpartum mice, whereas they were decreased in selenium-treated groups. GPX1, GPX4, and NRF2 expression were reduced in postpartum model mice, but upregulated in selenium- treated mice.</p><p><strong>Conclusion: </strong>Selenium supplementation ameliorated postpartum uterine oxidative stress and inflammation and promoted uterine recovery via the GPX1/GPX4/NRF2 pathway in mice.</p>","PeriodicalId":10881,"journal":{"name":"Current pharmaceutical biotechnology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential Pharmacological Ability of a Novel Marine Polysaccharide Extracted from Tunisian Green Algae Chaetomorpha aerea to Accelerate Dermal Wound Healing in Rats.","authors":"Marwa Kraiem, Malek Eleroui, Zakaria Boujhoud, Marwa Ajala, Marwa Bouhamed, Abderraouf Hilali, Hatem Kallel, Ibtissem Ben Amara","doi":"10.2174/0113892010309000240912110548","DOIUrl":"https://doi.org/10.2174/0113892010309000240912110548","url":null,"abstract":"<p><strong>Background: </strong>Bacterial infection and oxidative stress generation are significant obstacles to dermal wound healing. The present study undertakes the isolation of a sulfated polysaccharide from the Tunisian green algal \"Chaetomorpha aerea\" named PCA.</p><p><strong>Methods: </strong>The polysaccharide PCA was structurally characterized using Fourier Transformed Infrared (FT-IR), and monosaccharide analysis was carried out by HPLC-FID X-ray diffraction (XRD) and Scanning Electron Microscopy (SEM). The antioxidant potential of polysaccharides extracted from the Chaetomorpha area was evaluated in vitro using various antioxidant assays, and the antibacterial activity of PCA against four Gram-negative bacteria was estimated. The wound healing capacity of PCA was evaluated in vivo using an excision wound model in rats.</p><p><strong>Results: </strong>FT-IR spectra revealed the characteristic bands of polysaccharides. HPLC-FID revealed a heteropolysaccharide composed of arabinose, glucose, glucuronic acid, and galactose units. Indeed, the X-ray diffraction revealed a semi-crystalline structure of PCA. The obtained data showed a strong antioxidant capacity and an interesting antibacterial activity against four-gram negative bacteria Escherichia coli, Acinetobacter baumannii, Klebsiella pneumonia, and Pseudomonas aeruginosa. These biological data strongly support the beneficial effects of PCA in accelerating wound healing in rats. The in vivo study on rats demonstrated that PCA significantly accelerated the wound healing process over an 11-day treatment period. The application of PCA on wounds led to enhanced collagen fiber synthesis, as evidenced by histological staining, which showed increased collagen deposition at the wound site. Additionally, PCA treatment resulted in faster wound closure, with measurements showing a marked reduction in wound size compared to control groups.</p><p><strong>Conclusion: </strong>The present study highlights the promising pharmacological effects of PCA, suggesting its potential application in wound dressings due to its robust antioxidant, antibacterial, and wound-healing properties.</p>","PeriodicalId":10881,"journal":{"name":"Current pharmaceutical biotechnology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges and Pathways in Regulating Next-Gen Biological Therapies.","authors":"Surendra Agrawal, Sunita Vaidya, Jitendra Patel, Pranita Jirvankar, Pravina Gurjar","doi":"10.2174/0113892010367028250411111549","DOIUrl":"https://doi.org/10.2174/0113892010367028250411111549","url":null,"abstract":"<p><strong>Background: </strong>Current medicine could benefit from gene and cell therapies for genetic defects, cancer, and degenerative disorders. These therapies modify genetic material or biological components. CRISPR-Cas9 gene editing, stem cell, and CAR-T treatments are examples. Complex products need rigorous regulations to ensure quality, efficacy, and patient safety.</p><p><strong>Objectives: </strong>This paper discusses international gene and cell-based treatment regulatory regimes, highlighting key issues and recent developments. It also includes gene and cell-based therapy classes and mechanisms.</p><p><strong>Method: </strong>The publications on gene and cell therapy challenges and their regulatory approvals in the US, Europe, Japan, Australia, Brazil, Canada, and China were collected over the last 20 years from PubMed, Scopus, and Google Scholar and analyzed to determine the differences.</p><p><strong>Results: </strong>Gene treatments correct genetic defects or disease processes by adding, removing, or changing cell genetic information. In contrast, cell-based therapies restore damaged tissues with modified or unmodified cells. Highly customized and patient-specific drugs make regulatory monitoring challenging. US FDA CBER controls gene and cell-based therapies. Before clinical trials, these biologic drugs must file BLAs for market approval and INDs.</p><p><strong>Discussion: </strong>FDA's Breakthrough Therapy and Regenerative Medicine Advanced Therapy (RMAT) designations accelerate biological development. The EMA oversees EU Advanced Therapy Medicinal Products. ATMP quality, safety, and efficacy are CAT's top priorities. The Conditional Marketing Authorization process expedites access to life-threatening disease medicines while the MAA regulates them. Japan's PMDA's Conditional Time-Limited Approval for regenerative medicines provides early commercialization and rigorous post-market supervision. Similarly, each country has adopted some ways to expedite the approval of biologicals. Geneediting drugs require specialized methods, long-term follow-up, and better safety to avoid offtarget effects. GMPs ensure production uniformity, sterility, and safety, complicating manufacturing and quality control.</p><p><strong>Conclusion: </strong>The review concludes that there is a need for worldwide regulatory harmonization and regulatory framework developments, including R.W.E., adaptive pathways, and personalization of biologics.</p>","PeriodicalId":10881,"journal":{"name":"Current pharmaceutical biotechnology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting Inhibitor Development in Hemophilia 'A' using Machine Learning: A Comprehensive Approach to Data Preprocessing, Balancing, and Biomarker Identification Using AI on the CHAMP Dataset.","authors":"Vikalp Kumar Singh, Maheshwari Prasad Singh","doi":"10.2174/0113892010366485250415101928","DOIUrl":"https://doi.org/10.2174/0113892010366485250415101928","url":null,"abstract":"<p><strong>Background: </strong>Hemophilia 'A' (HA) is a genetic blood disorder characterized by a deficiency of Factor VIII (FVIII), with treatment often triggering the development of neutralizing antibodies (inhibitors) to FVIII. Predicting the development of these inhibitors is crucial for clinical applications but presents significant computational challenges due to data imbalance, skewed data, and inadequate data sanitization.</p><p><strong>Objective: </strong>This study aimed to develop a machine-learning/AI approach to find biomarkers and predict the development of inhibitors to Factor VIII in patients with Hemophilia 'A,' addressing the challenges associated with data imbalance and enhancing prediction accuracy.</p><p><strong>Methods: </strong>The data were sanitized and encoded for prediction, and the Random Over-sampling (ROS) technique was employed to resolve data imbalance in the CHAMP dataset. Several machine- learning classification models, including Random Forest, XG Boost, Cat Boost, Logistic Regression, Gradient Boosting, and Light GBM, were utilized. Hyperparameters were tuned using GridSearchCV optimization with a stratified k-fold approach. The performance of the models was evaluated based on accuracy, precision, recall, and F1 scores. The Random Forest model was further analyzed using an explainable AI (XAI) tool known as SHAP (SHapley Additive exPlanations) to identify the variables influencing model performance.</p><p><strong>Results: </strong>The Random Forest model outperformed other classifiers, achieving a mean accuracy of 97.37%, along with closely aligned precision, recall, and F1 scores. The XAI tool SHAP facilitated the ranking of variables Clinical Severity, Variant Type, Exon, HGVS cDNA, hg19 Coordinates, and others according to their impact on the model's predictions. Additionally, the study identified biomarkers associated with FVIII inhibition.</p><p><strong>Conclusion: </strong>This study presents a breakthrough in the early prediction of inhibitor development in Hemophilia 'A' patients, paving the way for personalized and effective treatment programs. The integration of the preprocessing pipeline, Random Forest model, and SHAP analysis offers a novel solution for guiding treatment strategies for HA patients, which could significantly enhance the development of targeted and effective therapies.</p>","PeriodicalId":10881,"journal":{"name":"Current pharmaceutical biotechnology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbial Influences: The Microbiome's Impact on Pancreatic Cancer Development and Progression.","authors":"Md Fakruddin, Zarifah Chowdhury, Suraiya Nasrin Suprova, Bakhtiar Ul Islam, Jinath Sultana Jime, Nayeema Bulbul, Mohammad Badrul Anam, Shahnewaj Bin Mannan, Md Asaduzzaman Shishir","doi":"10.2174/0113892010356542250407143257","DOIUrl":"https://doi.org/10.2174/0113892010356542250407143257","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges due to its dense stromal environment, which impedes treatment efficacy. Recent molecular and phenotypic analyses have enhanced our understanding of PDAC, driving the development of targeted therapies. Emerging research highlights the crucial role of the pancreatic tumor microbiome in PDAC initiation and progression. However, the specific mechanisms influencing the tumor microenvironment (TME) and systemic immunity remain incompletely understood. Studies have elucidated various genetic mutations, signaling pathways, and cellular interactions driving PDAC progression, aiding the development of targeted therapies. Despite these advances, overall survival rates for PDAC patients remain low, necessitating novel therapeutic strategies. Therapeutic strategies targeting the microbiome hold significant potential. Therapeutic strategies aimed at modulating microbiomes demonstrate significant potential for treating diseases and enhancing human well-being. Early research indicates that manipulating the microbiome could alter the TME to enhance the efficacy of existing treatments and lead to new therapeutic modalities. Modulating microbiomes might improve the delivery and effectiveness of chemotherapeutic agents or sensitize the tumor to immunotherapy, potentially revolutionizing PDAC treatment paradigms. Microbes can indirectly contribute to pancreatic cancer by inducing chronic inflammation and immune dysregulation. Microbes create a pro-inflammatory environment conducive to cancer development. This persistent inflammation can lead to genetic mutations and a suppressed immune response, fostering an environment where cancer cells can thrive. This review synthesizes current evidence on how the microbiome influences PDAC development and progression, emphasizing its potential for early disease detection and novel therapeutic strategies. Early detection, particularly in premalignant conditions such as chronic pancreatitis and intraductal papillary mucinous neoplasm (IPMN), is crucial for improving patient outcomes through timely intervention.</p>","PeriodicalId":10881,"journal":{"name":"Current pharmaceutical biotechnology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Comprehensive 4-Layered In Silico Pharmacogenomics Analysis of the Genetic Addiction Risk Severity (GARS) Test: Strong Genetic Evidence Supporting GARS as a Novel Personalized Pre-Addiction Assessment Tool in the Opioid Crisis Era","authors":"Alireza Sharafshah, Kai-Uwe Lewandrowski, Igor Elman, David Baron, Panayotis K Thanos, Colin Hanna, Mark S Gold, Rajendra D Badgaiyan, Jean Lud Cadet, Edward J Modestino, Eric Braverman, Catherine A Dennen, Milan Makale, Keerthy Sunder, Kevin T Murphy, Abdalla Bowirrat, Albert Pinhasov, Marjorie Gondre-Lewis, Eliot Gardner, Daniel Sipple, Nicole Jafari, Foojan Zeine, Jag Khalsa, Rossano Kepler Alvim Fiorelli, Kenneth Blum","doi":"10.2174/0113892010353450250408114725","DOIUrl":"https://doi.org/10.2174/0113892010353450250408114725","url":null,"abstract":"<p><strong>Background: </strong>Overdose involving opioids is the black heart of the addiction crisis. \"Pre-addiction,\" as an encouraging concept by NIDA and NIAAA, seems best captured with the construct of dopamine dysregulation. Referring to the abundant publications on \"Reward Deficiency Syndrome\" (RDS), Genetic Addiction Risk Score (GARS) test, RDSQ29, and KB220, Pre-addiction can be referred to as \"reward dysregulation\" as a suitable suggestion. The hypothesis is that the true phenotype is RDS, and other behavioral disorders are endophenotypes where the genetic variants play important roles, specifically in the Brain Reward Cascade (BRC).</p><p><strong>Methods: </strong>This study tested the pharmacogenomics of the GARS panel by a multi-model in silico investigation in four layers: 1) Protein-Protein Interactions (PPIs); 2) Gene Regulatory Networks (GRNs); 3) Disease, drugs and chemicals (DDCs); and 4) Gene Coexpression Networks (GCNs).</p><p><strong>Results: </strong>All in silico findings were combined in an Enrichment Analysis for 59 refined genes, which represented highly significant associations of dopamine pathways in the BRC and supported our hypothesis.</p><p><strong>Conclusion: </strong>This paper provides scientific evidence for the importance of incorporating GARS as a predictive test to identify Pre-addiction, introduce unique therapeutic targets assisting in the treatment of pain, drug dosing of prescription pharmaceuticals, and identify the risk for subsequent addiction early in -life.</p>","PeriodicalId":10881,"journal":{"name":"Current pharmaceutical biotechnology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Mechanisms of Immune Resistance in Pancreatic Cancer: An Update.","authors":"Wei Ming Pang, Wei Meng Lim, Zi Ni Ngai, Rhun Yian Koh","doi":"10.2174/0113892010365485250330110031","DOIUrl":"https://doi.org/10.2174/0113892010365485250330110031","url":null,"abstract":"<p><p>Pancreatic cancer is an exceptionally aggressive form of cancer with a poor prognosis, primarily due to several factors, one of which is the significant development of immune resistance. Despite new medical perceptions of the interaction between the immune system and tumour, experts have continually explored the molecular mechanisms of immune resistance in pancreatic cancer over the years but have not yet reached a complete understanding. Studying immune resistance is also fundamental because it gives us a better understanding of how to develop highly effective, individualised immunotherapeutic approaches. However, various characteristics can be used to describe the degree of immunological resistance. In the case of pancreatic cancer, the Tumour Microenvironment (TME) is specially structured in a way that it consists of stroma abundantly. Concurrently, it can regulate the secretion and expression of various immunosuppressants, like programmed death-ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO), adenosine, and inosine that impairs the anti-tumour response attributed from the immune system, along with growth factors that contributes to the development of tumour growth. Besides, oncogenic pathways, such as TP53 and KRAS mutation and immunosuppressive cell populations, including T-regulating cells and myeloid-derived suppressor cells collaboratively suppress the immune activity, thereby inducing immune resistance. These complexities present significant challenges in designing effective treatments. Immune checkpoints and mechanisms such as PDL1- mediated MHC-1 downregulation, galectins, autophagy, TP53, and P2RX1-negative neutrophils also contribute to immune resistance. Hence, this review summarises the current knowledge regarding the underlying molecular mechanisms of immune resistance in pancreatic cancer, along with several existing molecular therapeutics and approaches to overcome these barriers.</p>","PeriodicalId":10881,"journal":{"name":"Current pharmaceutical biotechnology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}